Pancreatic cancer has one of the highest mortality rates of any malignancy, and the 5-year-survival rate of patients is 4%. Approximately 28,000 patients are diagnosed with pancreatic cancer each year, and nearly all patients will die of their disease (Greenlee, R. T., et al, (2001) CA Cancer J Clin, 51: 15-36). The poor prognosis of this malignancy is a result of the difficulty of early diagnosis and poor response to current therapeutic methods (Greenlee, R. T., et al. (2001) CA Cancer J Clin, 51: 15-36, Klinkenbijl, J. H., et al. (1999) Ann Surg, 230: 776-82; discussion 782-4.). In particular, there are currently no identified tumor markers that allow for reliable screening at an early, potentially curative stage of the disease.
Research aimed at elucidation of carcinogenic mechanisms has revealed a number of candidate target molecules for the development of anti-tumor agents. For example, the farnesyltransferase inhibitor (FTI) has been shown to be effective in the therapy of Ras-dependent tumors in animal models (Sun J et al., (1998) Oncogene, 16:1467-73.). This pharmaceutical agent was developed to inhibit growth signal pathways related to Ras, which is dependant on post-transcriptional farnesylation. Human clinical trials where anti-tumor agents were applied in combination with the anti-HER2 monoclonal antibody, trastuzumab, in order to antagonize the proto-oncogene HER2/neu have succeeded in improving clinical response, and improved the overall survival rate of breast cancer patients. Tyrosine kinase inhibitor STI-571 is an inhibitor which selectively deactivates bcr-abl fusion protein. This pharmaceutical agent was developed for the therapy of chronic myeloid leukemia, where the constant activation of bcr-abl tyrosine kinase plays a significant role in the transformation of white blood cells. Such pharmaceutical agents are designed to inhibit the carcinogenic activity of specific gene products (Molina M A, et al., (2000) Cancer Res, 16:4744-9). Thus, in cancer cells, gene products with promoted expression are generally potential targets for the development of novel anti-tumor agents.
Another cancer therapy strategy involves the use of antibodies which bind to cancer cells. The following are representative mechanisms of antibody-mediated cancer therapy:
Missile therapy: in this approach, a pharmaceutical agent is bound to an antibody that binds specifically to cancer cells, thereby allowing the agent to act specifically on the cancer cells. This targeted distribution allows even those agents with strong side effects to act intensively on the cancer cells. In addition to pharmaceutical agents, there are also reports of approaches where precursors of pharmaceutical agents, enzymes which metabolize the precursors to an active form, and so on are bound to the antibodies.
The use of antibodies which target functional molecules: this approach inhibits the binding between growth factors and cancer cells using, for example, antibodies that bind growth factor receptors or growth factors. Proliferation of some cancer cells is highly dependent on growth factors. For example, some cancers are known to be dependent on epithelial growth factor (EGF) or vascular endothelial growth factor (VEGF) for cell growth. For such cancers, inhibiting the binding between a growth factor and cancer cells can be expected to have a therapeutic effect.
Antibody cytotoxicity: antibodies that bind to certain kinds of antigens can achieve cytotoxicity in cancer cells. With these types of antibodies, the antibody molecule itself has a direct anti-tumor effect. Antibodies that display cytotoxicity to cancer cells are gaining attention as antibody agents expected to be highly effective against tumors.